Founded in October 1937 by the Presidents of Liberia and Sierra Leone, the MRU was formed mainly to promote the economic growth, social progress, and cultural advancement through trade promotion. The name Mano River Union (MRU) was derived from the River Mano which runs from the Guinea highlands, along the borders of Sierra Leone and Liberia.

In 1980, Guinea joined the union and together, these three countries collaborated to accelerate economic growth as well as promote mutual assistance in matters of common interest to the three countries.

The Mano River Union was however unable to achieve its initial objectives due to the 1991-2003 civil wars in the two original member countries. By the end of 2000 the staff was down to 48, from the initial 600.

In May 2004, the Union reactivated at a summit of the three leaders of the Mano River Union Countries. Cote d’Ivoire subsequently agreed to join the Union in 2008 and these four countries together share borders and make up the MRU Sub-region. These countries have significant historical, cultural, and social similarities, traditions, and a common tribal makeup.